Malaria is caused by eukaryotic parasites that display distinct surface antigens during three independent stages of the life cycle: initial infection caused by the pre-erythrocytic (PE) stage, clinical symptoms as a result of the blood stage, and transmission by the mosquito stage. While both T-cell and B-cell responses play a role in naturally acquired immunity to malaria, focusing the B-cell responses on conserved broadly-neutralizing functional epitopes significantly improves protection and may lead to sterile immunity. Three aspects of parasite biology confound malaria vaccine development: (1) antigenic variability, (2) the presence of immunodominant but non-neutralizing epitopes in antigens, and (3) the diverse and numerous parasite antigens required for each stage of the life cycle. The explosion in technology for structural vaccinology and the structural definition of neutralizing epitopes in key malaria antigens motivates the structure-guided design of immunogens for malaria vaccine development. We propose to reliably identify neutralizing-antibody epitopes and define the components required to elicit a strongly-neutralizing immune response to malaria. These studies would form the basis for creating novel engineered immunogens that will harness the immune system to protect against P. falciparum and P. vivax the two species that cause the majority of malaria cases. In recent years, parasite surface proteins have been identified that are required for parasite viability and have the potential to elicit a neutralizing antibody response. While it is clear that antibodies targeting these surface proteins can reduce invasion, only a subset of antibodies that bind to these vaccine candidates are neutralizing. In addition, a complete halt of disease progression will require targeting multiple parasite proteins simultaneously, due to the functional redundancy within and across protein families available to the parasite. There is a significant gap in our understanding of the neutralizing potential of epitopes. In the absence of this knowledge, efficient vaccine design to prevent the pathogenesis of malaria will be severely hampered. Our prior work has demonstrated that strongly-neutralizing antibodies recognize epitopes in functional regions of parasite proteins (for example oligomerization interfaces or receptor binding residues) rendering ligands non-functional, while non-neutralizing or weakly-neutralizing antibodies bind to non-functional regions. Thus, identifying strongly-neutralizing epitopes and eliminating weakly- or non-neutralizing epitopes is fundamental to designing an effective malaria vaccine. Once strongly-neutralizing epitopes have been identified these will be exploited for vaccine design, protein-based therapeutics and/or diagnostics.